Cosmetic use of N-substituted sulfonyloxybenzylamines and related compounds

ABSTRACT

Cosmetic compositions comprising N-substituted sulfonyloxybenzylamines and methods of using such compositions to impart anti-aging benefits to the skin are disclosed. The N-substituted sulfonyloxybenzylamines are believed to have modulatory activity against one or more biochemical pathways implicated in skin aging.

FIELD OF INVENTION

The present invention relates generally to compositions for topicalapplication to the skin which comprise N-substitutedsulfonyloxybenzylamines and the use of such compositions to improve theaesthetic appearance of the skin.

BACKGROUND OF THE INVENTION

Collagen is the body's major structural protein and is composed of threeprotein chains wound together in a tight triple helix. This uniquestructure gives collagen a greater tensile strength than steel.Approximately 33 percent of the protein in the body is collagen. Thisprotein supports tissues and organs and connects these structures tobones. In fact, bones are also composed of collagen combined withcertain minerals such as calcium and phosphorus. Collagen plays a keyrole in providing the structural scaffolding surrounding cells thathelps to support cell shape and differentiation, similar to how steelrods reinforce a concrete block. The mesh-like collagen network bindscells together and provides the supportive framework or environment inwhich cells develop and function, and tissues and bones heal.

Collagen is created by fibroblasts, which are specialized skin cellslocated in the dermis. Fibroblasts also produce other skin structuralproteins such as elastin (a protein which gives the skin its ability tosnap back) and glucosaminoglycans (GAGs). GAGs make up the groundsubstance that keeps the dermis hydrated. In order to signal or turn onthe production of skin structural proteins, fibroblast cells havespecially shaped receptors on their outside membranes that act asbinding sites to which signal molecules with a matching shape can fit.When the receptors are bound by the correct combination of signalmolecules (called fibroblast growth factors, or FGFs), the fibroblastbegins the production of collagen. The stimulation of collagen gives theskin its strength, durability, and smooth, plump appearance.

The invention thus provides new compositions and methods for stimulatingcollagen production. It is a further object of the invention to improvethe overall appearance of skin, including treating, reversing, and/orpreventing signs of aging, such as skin wrinkles, by stimulatingcollagen production with cosmetic compositions comprising effectiveamounts of N-substituted sulfonyloxybenzylamines.

The foregoing discussion is presented solely to provide a betterunderstanding of nature of the problems confronting the art and shouldnot be construed in any way as an admission as to prior art nor shouldthe citation of any reference herein be construed as an admission thatsuch reference constitutes “prior art” to the instant application.

SUMMARY OF THE INVENTION

In accordance with the foregoing objectives and others, it hassurprisingly been found that N-substituted sulfonyloxybenzylamines arepotent stimulators of collagen production and thus are beneficial agentsagainst various signs of intrinsic aging and photo-aging of skin.

In one aspect of the invention, a method is provided for improving theaesthetic appearance of human skin comprising topically applying to anarea of the skin in need thereof an effective amount of an N-substitutedsulfonyloxybenzylamine or a cosmetically acceptable salt thereof in acosmetically acceptable vehicle.

In another aspect of the invention, cosmetic compositions are providedfor improving the aesthetic appearance of skin comprising, in acosmetically acceptable vehicle, an effective amount of an N-substitutedsulfonyloxybenzylamine having the structure of formula I:

where W₁, W₂ are independently CO, CO₂, CONH, SO₂ or PO₃;

R₁, R₂ and R₃ are independently C₁₋₂₀ hydrocarbons, each independentlyselected from alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, heteroalkyl,aryl, arylalkyl, alkylaryl, heteroarylalkyl, and alkylheteroaryl, andeach being optionally substituted with C and/or 1-6 heteroatoms,selected from halogens, O, N, S, and with S optionally being oxidized;

X, Y each independently represent H or an optionally substituted alkyl,haloalkyl, alkoxy, amino, aminoalkyl, haloalkoxy, alkenyl, and whereadjacent X, Y taken together can form a 5, 6, or 7 member ring;

R₁, R₂ and R₃ each may also be optionally substituted with, for example,amino, aminoalkyl, alkoxy, haloalkoxy, haloalkyl, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, etc.

and wherein the —O—W₂—R₁ group is attached to the phenyl ring at the 2-,3- or 4-position.

Also provided is a method of treating one or more signs of skin agingcomprising topically applying to skin in need thereof an N-substitutedsulfonyloxybenzylamine according to formula I in an amount effective toenhance collagen.

In another aspect of the invention, a method of treating, ameliorating,and/or preventing fine lines or wrinkles or sagging in human skin isprovided, comprising topically applying to skin in need thereof,including applying directly to a wrinkle or fine line, a compositioncomprising a N-substituted sulfonyloxybenzylamine according to formula Iin an amount effective to enhance collagen.

These and other aspects of the present invention will be betterunderstood by reference to the following detailed description andaccompanying figures.

DETAILED DESCRIPTION

All terms used herein are intended to have their ordinary meaning unlessotherwise provided.

The present invention provides compositions for topical applicationwhich comprise and effective amount of N-substitutedsulfonyloxybenzylamines or a related compound to treat, reverse,ameliorate and/or prevent signs of skin aging. Such signs of skin aginginclude without limitation, the following:

(a) treatment, reduction, and/or prevention of fine lines or wrinkles,

(b) reduction of skin pore size,

(c) improvement in skin thickness, plumpness, and/or tautness;

(d) improvement in skin suppleness and/or softness;

(e) improvement in skin tone, radiance, and/or clarity;

(f) improvement in procollagen and/or collagen production;

(g) improvement in maintenance and remodeling of elastin;

(h) improvement in skin texture and/or promotion of retexturization;

(i) improvement in skin barrier repair and/or function;

(j) improvement in appearance of skin contours;

(k) restoration of skin luster and/or brightness;

(l) replenishment of essential nutrients and/or constituents in theskin;

(m) decreased by aging and/or menopause;

(n) improvement in skin moisturization;

(o) increase in skin elasticity and/or resiliency;

(p) treatment, reduction, and/or prevention of skin sagging and/or

(q) reduction of pigment spots.

In practice, the compositions of the invention are applied to skin inneed of treatment. That is, skin which suffers from a deficiency or lossin any of the foregoing attributes or which would otherwise benefit fromimprovement in any of the foregoing skin attributes.

In certain preferred embodiments the compositions and methods of theinvention are directed to the prevention, treatment, and/or ameliorationof fine lines and/or wrinkles in the skin. In this case, thecompositions are applied to skin in need of treatment, by which is meantskin having wrinkles and/or fine lines. Preferably, the compositions areapplied directly to the fine lines and/or wrinkles. The compositions and

The cosmetic compositions for treating a skin condition associated withloss of collagen and/or elastin fiber comprise, in a cosmeticallyacceptable vehicle, an amount of a N-substituted sulfonyloxybenzylamineseffective to enhance collagen. These collagen enhancing agents may havethe structure of formula (I):

In formula (I), W₁ and W₂ are independently CO, CO₂, CONH, SO₂, or PO₃;R₁, R₂ and R₃ are independently alkyl, cycloalkyl, haloalkyl,alkoxyalkyl, arylaklyl or heteroalkyl, each which may be optionallysubstituted with C and/or 1-6 heteroatoms, selected from halogens, O, N,S, and with S optionally being oxidized; X, Y each independentlyrepresent H or are optionally substituted alkyl, haloalkyl, alkoxy,amino, aminoalkyl, haloalkoxy, alkenyl, and where adjacent X, Y takentogether can form a 5, 6, or 7 member ring.

In one embodiment, W₁ and W₂ are SO₂, X and Y are H; R₁, R₂ eachrepresent C₁-C₈ alkyl, preferably C₁-C₄ alkyl, and R₃ is an aliphaticalkyl, C₁-C₈ substituted or unsubstituted cycloalkyl, or an aromatichydrocarbon radical, as exemplified by C₆ aromatic hydrocarbon radicalwhich may be a substituted or unsubstituted aryl (e.g., phenyl). Inother embodiments R₁, R₂, R₃ independently represent a lower alkyl group(e.g., methyl, ethyl, propyl, butyl, etc.), typically methyl or ethyl).In other embodiments, R₁, R₂ represent, independently at each occurrencealiphatic C₁-C₈ hydrocarbon radicals; including aliphatic C₁-C₆hydrocarbon radicals, aliphatic C₁-C₈ hydrocarbon radicals, or analiphatic C₁-C₆ hydrocarbon radicals, as exemplified by substituted orunsubstituted branched, straight chain or cyclic, alkyl, alkenyl (e.g.,vinyl, allyl, etc.), and alkynyl moieties; C₆-C₂₀ aromatic hydrocarbonradicals, including C₆-C₁₂ aromatic hydrocarbon radicals, C₆-C₁₀aromatic hydrocarbon radicals, or C₆ aromatic hydrocarbon radicals, asexemplified by substituted or unsubstituted aryl (e.g., phenyl),alkyl-aryl (e.g., benzyl), aryl-alkyl, and the like; or C₁-C₂₀heteroaryl radicals including one or more heteroatoms selected from O,N, and S in the ring; including C₁-C₁₂ heteroaromatic radicals, C₁-C₈heteroaromatic radicals, and C₁-C₆ heteroaromatic radicals, asexemplified by heteroaryl, alkyl-heteroaryl, heteroarylalkyl and thelike.

R₁, R₂ and R₃ each may also be optionally substituted with, for example,amino, aminoalkyl, alkoxy, haloalkoxy, haloalkyl, halogen, amino,aminoalkyl, alkoxy, haloalkoxy, haloalkyl, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, etc.

In some embodiments, W₁ is CONH, W₂ is SO₂, X and Y are H, R₁ is C₁-C₈alkyl, R₂ is C₁-C₈ alkyl or aralkyl, and R₃ is alkyl, cycloalkyl,arylalkyl or heteroalkyl.

In other embodiments, W₁ represents a carbonyl group —(C═O)—, W₂ is SO₂,X and Y are H, R₁ is C₁-C₈ alkyl, R₂ is C₁-C₈ alkyl or arylalkyl, and R₃is alkyl, cycloalkyl, arylalkyl or heteroalkyl.

Further, any nitrogen atom may be optionally oxidized to the N-oxide orcan be quarternized, for example with lower alkyl halides, such asmethyl, ethyl, propyl, and butyl chloride, bromides, and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides such as benzyl andphenethyl bromides, to name a few.

In one embodiment according to formula (I), W₁ and W₂ are SO₂, as shownin formula (Ia).

where X and Y are H, R₁ is an alkyl group, R₂ is i-butyl and R₃ is aphenyl group.

In another embodiment, W₁ is SO₂ and W₂ will be a group —CONH—, X and Yare H, R₁ is an alkyl group, R₂ is an alkyl group and R₃ is substitutedphenyl group as shown in formula (Ib):

where the —OSO₂R₁ group is positioned on the phenyl ring at position 3-or 4-. Preferably R is a methyl group, R₂ is isobutyl and R₃ is a2-ethyl phenyl group.

In a further embodiment, W₁ is a be a carbonyl group (—CO—), W₂ is SO₂,X and Y are H, R₁ is an alkyl group, R₂ is alkyl group and R₃ is analkyl group or substituted phenyl group as shown in formula (Ic):

where R₁ is preferably methyl, R₂ is an alkyl group or an alkoxy groupand R₃ is a substituted phenyl group.

In a particular embodiment, a cosmetic composition comprises, in acosmetically acceptable vehicle, preferably a water-in-oil oroil-in-water emulsion, from about 0.0001% to about 90% by weight of aN-substituted sulfonyloxybenzylamine having the structure:

or a cosmetically acceptable salt thereof.

In another particular embodiment, a cosmetic composition comprises, in acosmetically acceptable vehicle, preferably a water-in-oil oroil-in-water emulsion, from about 0.0001% to about 90% by weight of aN-substituted sulfonyloxybenzylamine having the structure:

or a cosmetically acceptable salt thereof.

The invention embraces the use of cosmetically or pharmaceuticallyacceptable (e.g., non-toxic and/or non-irritating) salts. Examples ofthe salts of the compounds in the present invention include salts withalkali metals such as sodium and potassium; salts with alkaline-earthmetals such as calcium and magnesium; salts with amines such asmonoethanolamine; salts with inorganic acids such as hydrochloric acidand sulfuric acid; and salts with organic acids such as citric acid andacetic acid. Special mention may be made of hydrochloride salts.

The cosmetic compositions according to the invention can be formulatedin a variety of forms for topical application and will comprise fromabout 0.00001% to about 90% by weight of one or more compounds accordingto formula (I), and preferably will comprise from about 0.001% to about25% by weight, and more preferably from about 0.001% to about 1% byweight. The compositions will comprise an effective amount of theN-substituted sulfonyloxybenzylamine compounds according to formula (I),by which is meant an amount sufficient to enhance collagen in s givenarea of skin when topically applied thereto.

The composition may be formulated in a variety of product forms, suchas, for example, a lotion, cream, serum, spray, aerosol, cake, ointment,essence, gel, paste, patch, pencil, towelette, mask, stick, foam,elixir, concentrate, and the like, particularly for topicaladministration. Preferably the composition is formulated as a lotion,cream, ointment, or gel.

The compositions can include a cosmetically acceptable vehicle. Suchvehicles may take the form of any known in the art suitable forapplication to skin and may include, but are not limited to, water;vegetable oils; mineral oils; esters such as octal palmitate, isopropylmyristate and isopropyl palmitate; ethers such as dicapryl ether anddimethyl isosorbide; alcohols such as ethanol and isopropanol; fattyalcohols such as cetyl alcohol, cetearyl alcohol, stearyl alcohol andbiphenyl alcohol; isoparaffins such as isooctane, isododecane and ishexadecane; silicone oils such as cyclomethicone, dimethicone,dimethicone cross-polymer, polysiloxanes and their derivatives,preferably organomodified derivatives; hydrocarbon oils such as mineraloil, petrolatum, isoeicosane and polyisobutene; polyols such aspropylene glycol, glycerin, butylene glycol, pentylene glycol andhexylene glycol; waxes such as beeswax and botanical waxes; or anycombinations or mixtures of the foregoing.

The vehicle may comprise an aqueous phase, an oil phase, an alcohol, asilicone phase or mixtures thereof. The cosmetically acceptable vehiclemay also comprise an emulsion. Non-limiting examples of suitableemulsions include water-in-oil emulsions, oil-in-water emulsions,silicone-in-water emulsions, water-in-silicone emulsions, wax-in-wateremulsions, water-oil-water triple emulsions or the like having theappearance of a cream, gel or microemulsions. The emulsion may includean emulsifier, such as a nonionic, anionic or amphoteric surfactant.

The oil phase of the emulsion preferably has one or more organiccompounds, including emollients; humectants (such as propylene glycoland glycerin); other water-dispersible or water-soluble componentsincluding thickeners such as veegum or hydroxyalkyl cellulose; gellingagents, such as high MW polyacrylic acid, i.e. CARBOPOL 934; andmixtures thereof. The emulsion may have one or more emulsifiers capableof emulsifying the various components present in the composition.

The compounds suitable for use in the oil phase include withoutlimitation, vegetable oils; esters such as octyl palmitate, isopropylmyristate and isopropyl palmitate; ethers such as dicapryl ether; fattyalcohols such as cetyl alcohol, stearyl alcohol and behenyl alcohol;isoparaffins such as isooctane, isododecane and isohexadecane; siliconeoils such as dimethicones, cyclic silicones, and polysiloxanes;hydrocarbon oils such as mineral oil, petrolatum, isoeicosane andpolyisobutene; natural or synthetic waxes; and the like. Suitablehydrophobic hydrocarbon oils may be saturated or unsaturated, have analiphatic character and be straight or branched chained or containalicyclic or aromatic rings. The oil-containing phase may be composed ofa singular oil or mixtures of different oils.

Hydrocarbon oils include those having 6-20 carbon atoms, more preferably10-16 carbon atoms. Representative hydrocarbons include decane,dodecane, tetradecane, tridecane, and C₈₋₂₀ isoparaffins. Paraffinichydrocarbons are available from Exxon under the ISOPARS trademark, andfrom the Permethyl Corporation. In addition, C₈₋₂₀ paraffinichydrocarbons such as C₁₂ isoparaffin (isododecane) manufactured by thePermethyl Corporation having the tradename Permethyl 99ATM are alsocontemplated to be suitable. Various commercially available C₁₆isoparaffins, such as isohexadecane (having the tradename Permethyl®)are also suitable. Examples of preferred volatile hydrocarbons includepolydecanes such as isododecane and isodecane, including for example,Permethyl-99A (Presperse Inc.) and the C₇-C₈ through C₁₂-C₁₅isoparaffins such as the Isopar Series available from Exxon Chemicals. Arepresentative hydrocarbon solvent is isododecane.

The oil phase may comprise one or more waxes, including for example,rice bran wax, carnauba wax, ouricurry wax, candelilla wax, montanwaxes, sugar cane waxes, ozokerite, polyethylene waxes, Fischer-Tropschwaxes, beeswax, microcrystalline wax, silicone waxes, fluorinated waxes,and any combination thereof.

Non-limiting emulsifiers included emulsifying waxes, emulsifyingpolyhydric alcohols, polyether polyols, polyethers, mono- or di-ester ofpolyols, ethylene glycol mono-stearates, glycerin mono-stearates,glycerin di-stearates, silicone-containing emulsifiers, soya sterols,fatty alcohols such as cetyl alcohol, fatty acids such as stearic acid,fatty acid salts, and mixtures thereof. The preferred emulsifiersinclude soya sterol, cetyl alcohol, stearic acid, emulsifying wax, andmixtures thereof. Other specific emulsifiers that can be used in thecomposition of the present invention include, but are not limited to,one or more of the following: sorbitan esters;polyglyceryl-3-diisostearate; sorbitan monostearate, sorbitantristearate, sorbitan sesquioleate, sorbitan monooleate; glycerol esterssuch as glycerol monostearate and glycerol monooleate; polyoxyethylenephenols such as polyoxyethylene octyl phenol and polyoxyethylene nonylphenol; polyoxyethylene ethers such as polyoxyethylene cetyl ether andpolyoxyethylene stearyl ether; polyoxyethylene glycol esters;polyoxyethylene sorbitan esters; dimethicone copolyols; polyglycerylesters such as polyglyceryl-3-diisostearate; glyceryl laurate;Steareth-2, Steareth-10, and Steareth-20, to name a few. Additionalemulsifiers are provided in the INCI Ingredient Dictionary and Handbook11th Edition 2006, the disclosure of which is hereby incorporated byreference.

These emulsifiers typically will be present in the composition in anamount from about 0.001% to about 10% by weight, in particular in anamount from about 0.01% to about 5% by weight, and more preferably,below 1% by weight.

The oil phase may comprise one or more volatile and/or non-volatilesilicone oils. Volatile silicones include cyclic and linear volatiledimethylsiloxane silicones. In one embodiment, the volatile siliconesmay include cyclodimethicones, including tetramer (D4), pentamer (D5),and hexamer (D6) cyclomethicones, or mixtures thereof. Particularmention may be made of the volatile cyclomethicone-hexamethylcyclotrisiloxane, octamethyl-cyclotetrasiloxane, anddecamethyl-cyclopentasiloxane. Suitable dimethicones are available fromDow Corning under the name Dow Corning 200® Fluid and have viscositiesranging from 0.65 to 600,000 centistokes or higher. Suitable non-polar,volatile liquid silicone oils are disclosed in U.S. Pat. No. 4,781,917,herein incorporated by reference in its entirety. Additional volatilesilicones materials are described in Todd et al., “Volatile SiliconeFluids for Cosmetics”, Cosmetics and Toiletries, 91:27-32 (1976), hereinincorporated by reference in its entirety. Linear volatile siliconesgenerally have a viscosity of less than about 5 centistokes at 25° C.,whereas the cyclic silicones have viscosities of less than about 10centistokes at 25° C. Examples of volatile silicones of varyingviscosities include Dow Corning 200, Dow Corning 244, Dow Corning 245,Dow Corning 344, and Dow Corning 345, (Dow Corning Corp.); SF-1204 andSF-1202 Silicone Fluids (G.E. Silicones), GE 7207 and 7158 (GeneralElectric Co.); and SWS-03314 (SWS Silicones Corp.). Linear, volatilesilicones include low molecular weight polydimethylsiloxane compoundssuch as hexamethyldisiloxane, octamethyltrisiloxane,decamethyltetrasiloxane, and dodecamethylpentasiloxane, to name a few.

Non-volatile silicone oils will typically comprise polyalkylsiloxanes,polyarylsiloxanes, polyalkylarylsiloxanes, or mixtures thereof.Polydimethylsiloxanes are preferred non-volatile silicone oils. Thenon-volatile silicone oils will typically have a viscosity from about 10to about 60,000 centistokes at 25° C., preferably between about 10 andabout 10,000 centistokes, and more preferred still between about 10 andabout 500 centistokes; and a boiling point greater than 250° C. atatmospheric pressure. Non limiting examples include dimethylpolysiloxane (dimethicone), phenyl trimethicone, anddiphenyldimethicone. The volatile and non-volatile silicone oils mayoptionally be substituted will various functional groups such as alkyl,aryl, amine groups, vinyl, hydroxyl, haloalkyl groups, alkylaryl groups,and acrylate groups, to name a few.

The water-in-silicone emulsion may be emulsified with a nonionicsurfactant (emulsifier) such as, for example,polydiorganosiloxane-polyoxyalkylene block copolymers, including thosedescribed in U.S. Pat. No. 4,122,029, the disclosure of which is herebyincorporated by reference. These emulsifiers generally comprise apolydiorganosiloxane backbone, typically polydimethylsiloxane, havingside chains comprising -(EO)m- and/or —(PO)n-groups, where EO isethyleneoxy and PO is 1,2-propyleneoxy, the side chains being typicallycapped or terminated with hydrogen or lower alkyl groups (e.g., C₁₋₆,typically C₁₋₃). Other suitable water-in-silicone emulsifiers aredisclosed in U.S. Pat. No. 6,685,952, the disclosure of which is herebyincorporated by reference herein. Commercially availablewater-in-silicone emulsifiers include those available from Dow Corningunder the trade designations 3225C and 5225C FORMULATION AID; SILICONESF-1528 available from General Electric; ABIL EM 90 and EM 97, availablefrom Goldschmidt Chemical Corporation (Hopewell, Va.); and the SILWETseries of emulsifiers sold by OSI Specialties (Danbury, Conn.).

Examples of water-in-silicone emulsifiers include, but are not limitedto, dimethicone PEG 10/15 crosspolymer, dimethicone copolyol, cetyldimethicone copolyol, PEG-15 lauryl dimethicone crosspolymer,laurylmethicone crosspolymer, cyclomethicone and dimethicone copolyol,dimethicone copolyol (and) caprylic/capric triglycerides, polyglyceryl-4isostearate (and) cetyl dimethicone copolyol (and) hexyl laurate, anddimethicone copolyol (and) cyclopentasiloxane. Preferred examples ofwater-in-silicone emulsifiers include, without limitation, PEG/PPG-18/18dimethicone (trade name 5225C, Dow Corning), PEG/PPG-19/19 dimethicone(trade name BY25-337, Dow Corning), Cetyl PEG/PPG-10/1 dimethicone(trade name Abil EM-90, Goldschmidt Chemical Corporation), PEG-12dimethicone (trade name SF 1288, General Electric), lauryl PEG/PPG-18/18methicone (trade name 5200 FORMULATION AID, Dow Corning), PEG-12dimethicone crosspolymer (trade name 9010 and 9011 silicone elastomerblend, Dow Corning), PEG-10 dimethicone crosspolymer (trade name KSG-20,Shin-Etsu), and dimethicone PEG-10/15 crosspolymer (trade name KSG-210,Shin-Etsu).

The water-in-silicone emulsifiers typically will be present in thecomposition in an amount from about 0.001% to about 10% by weight, inparticular in an amount from about 0.01% to about 5% by weight, and morepreferably, below 1% by weight.

The aqueous phase of the emulsion may include one or more additionalsolvents, including lower alcohols, such as ethanol, isopropanol, andthe like. The volatile solvent may also be a cosmetically acceptableester such as butyl acetate or ethyl acetate; ketones such as acetone orethyl methyl ketone; or the like.

The oil-containing phase will typically comprise from about 10% to about99%, preferably from about 20% to about 85%, and more preferably fromabout 30% to about 70% by weight, based on the total weight of theemulsion, and the aqueous phase will typically comprise from about 1% toabout 90%, preferably from about 5% to about 70%, and more preferablyfrom about 20% to about 60% by weight of the total emulsion. The aqueousphase will typically comprise from about 25% to about 100%, moretypically from about 50% to about 95% by weight water.

The compositions may include liposomes. The liposomes may comprise otheradditives or substances and/or may be modified to more specificallyreach or remain at a site following administration.

Additionally, the compositions may incorporate encapsulation and/ormicroencapsulation technology. As is well known in the art,encapsulating materials can be selected which will release thecomposition upon exposure to moisture, pH change, temperature change,solubility change, or mechanical shear or rupture. Suitableencapsulating materials and methods of preparing encapsulated materials,such as spray drying, extrusion, coacervation, fluidized bed coating,liposome entrapment and others, are disclosed in, for example, U.S.Patent Application Publication No. 2005/0000531 to Shi; Uhlmann, et al.,“Flavor encapsulation technologies: an overview including recentdevelopments” Perfumer and Flavorist, 27, 52-61, 2002; and “Selection ofCoating and Microencapsulation Processes” by Robert E. Sparks and IrwinJacobs in Controlled-Release Delivery Systems for Pesticides, Herbert B.Scher ed., Marcel Dekker, New York, N.Y., 1999, pp. 3-29, the contentsof which are hereby incorporated by reference.

The compositions incorporating encapsulation and/or microencapsulationtechnology may form nanoparticles. The term “nanoparticle” as usedherein refers to a nanometer-sized particle, having a diameter ofbetween about 1 nanometer and about 999 nanometers; the term“nanoparticles” as used herein refers to nanometer-sized particles,nanoclusters, clusters, particles, small particles, and nanostructuredmaterials.

The composition may optionally comprise other cosmetic actives andexcipients, obvious to those skilled in the art including, but notlimited to, fillers, emulsifying agents, antioxidants, surfactants, filmformers, chelating agents, gelling agents, thickeners, emollients,humectants, moisturizers, vitamins, minerals, viscosity and/or rheologymodifiers, sunscreens, keratolytics, depigmenting agents, retinoids,hormonal compounds, alpha-hydroxy acids, alpha-keto acids,anti-mycobacterial agents, antifungal agents, antimicrobials,antivirals, analgesics, lipidic compounds, anti-allergenic agents, H1 orH2 antihistamines, anti-inflammatory agents, anti-irritants,antineoplastics, immune system boosting agents, immune systemsuppressing agents, anti-acne agents, anesthetics, antiseptics, insectrepellents, skin cooling compounds, skin protectants, skin penetrationenhancers, exfollients, lubricants, fragrances, colorants, depigmentingagents, hypopigmenting agents, preservatives, stabilizers,pharmaceutical agents, photostabilizing agents, sunscreens, and mixturesthereof. In addition to the foregoing, the cosmetic compositions of theinvention may contain any other compound for the treatment of skindisorders.

Colorants may include, for example, organic and inorganic pigments andpearlescent agents. Suitable inorganic pigments include, but are notlimited to, titanium oxide, zirconium oxide and cerium oxide, as well aszinc oxide, iron oxide, chromium oxide and ferric blue. Suitable organicpigments include barium, strontium, calcium, and aluminium lakes andcarbon black. Suitable pearlescent agents include mica coated withtitanium oxide, with iron oxide, or with natural pigment.

Various fillers and additional components may be added. Fillers arenormally present in an amount of about 0 weight % to about 20 weight %,based on the total weight of the composition, preferably about 0.1weight % to about 10 weight %. Suitable fillers include withoutlimitation silica, treated silica, talc, zinc stearate, mica, kaolin,Nylon powders such as Orgasol™, polyethylene powder, Teflon™, starch,boron nitride, copolymer microspheres such as Expancel™ (NobelIndustries), Polytrap™ (Dow Corning) and silicone resin microbeads(Tospearl™ from Toshiba), and the like.

In one embodiment of the invention, the compositions may includeadditional skin actives such as, but are not limited to, botanicals,keratolytic agents, desquamating agents, keratinocyte proliferationenhancers, collagenase inhibitors, elastase inhibitors, depigmentingagents, anti-inflammatory agents, steroids, anti-acne agents,antioxidants, salicylic acid or salicylates, thiodipropionic acid oresters thereof, and advanced glycation end-product (AGE) inhibitors.

In a specific embodiment, the composition may comprise at least oneadditional botanical, such as, for example, a botanical extract, anessential oil, or the plant itself. Suitable botanicals include, withoutlimitation, extracts from Abies pindrow, Acacia catechu, Aloe,Amorphophallus campanulatus, Anogeissus latifolia, Asmunda japonica,Azadirachta indica, Butea frondosa, Butea monosperma, Cedrus deodara,Chamomile, Emblica officinalis, Ficus benghalensis, Glycyrrhiza glabra,Humilus scandens, Ilex purpurea Hassk, Innula racemosa, Ligusticumchiangxiong, Ligusticum lucidum, Mallotus philippinensis, Melicopehayesil, Mimusops elengi, Morinda citrifolia, Moringa oleifera, Naringicrenulata, Nerium indicum, Piper betel, Pouzolzia petandra, Psoraleacorylifolia, Rhinacanthus nasutus, Sapindus rarek, Sesbania grandiflora,Stenoloma chusana, Terminalia bellerica, tomato glycolipid and mixturesthereof.

The composition may comprise additional active ingredients havinganti-aging benefits, as it is contemplated that synergistic improvementsmay be obtained with such combinations. Exemplary anti-aging componentsinclude, without limitation, botanicals (e.g., Butea Frondosa extract);phytol, thiodipropionic acid (TDPA) and esters thereof; retinoids (e.g.,all-trans retinoic acid, 9-cis retinoic acid, phytanic acid and others);hydroxy acids (including alpha-hydroxyacids and beta-hydroxyacids),salicylic acid and salicylates; exfoliating agents (e.g., glycolic acid,3,6,9-trioxaundecanedioic acid, etc.), estrogen synthetase stimulatingcompounds (e.g., caffeine and derivatives); compounds capable ofinhibiting 5 alpha-reductase activity (e.g., linolenic acid, linoleicacid, finasteride, and mixtures thereof); barrier function enhancingagents (e.g., ceramides, glycerides, cholesterol and its esters,alpha-hydroxy and omega-hydroxy fatty acids and esters thereof, etc.);collagenase inhibitors; and elastase inhibitors; to name a few.

Exemplary retinoids include, without limitation, retinoic acid (e.g.,all-trans or 13-cis) and derivatives thereof, retinol (Vitamin A) andesters thereof, such as retinol palmitate, retinol acetate and retinolpropionate, and salts thereof.

In another embodiment, the topical compositions of the present inventionmay also include one or more of the following: a skin penetrationenhancer, an emollient, a skin plumper, an optical diffuser, asunscreen, an exfoliating agent, and an antioxidant.

An emollient provides the functional benefits of enhancing skinsmoothness and reducing the appearance of fine lines and coarse wrinklesExamples include isopropyl myristate, petrolatum, isopropyl lanolate,silicones (e.g., methicone, dimethicone), oils, mineral oils, fatty acidesters, or any mixtures thereof. The emollient may be preferably presentfrom about 0.1 wt % to about 50 wt % of the total weight of thecomposition.

A skin plumper serves as a collagen enhancer to the skin. An example ofa suitable, and preferred, skin plumper is palmitoyl oligopeptide. Otherskin plumpers are collagen and/or other glycosaminoglycan (GAG)enhancing agents. When present, the skin plumper may comprise from about0.1 wt % to about 20 wt % of the total weight of the composition.

An optical diffuser is a particle that changes the surface optometricsof skin, resulting in a visual blurring and softening of, for example,lines and wrinkles Examples of optical diffusers that can be used in thepresent invention include, but are not limited to, boron nitride, mica,nylon, polymethylmethacrylate (PMMA), polyurethane powder, sericite,silica, silicone powder, talc, Teflon, titanium dioxide, zinc oxide, orany mixtures thereof. When present, the optical diffuser may be presentfrom about 0.01 wt % to about 20 wt % of the total weight of thecomposition.

A sunscreen for protecting the skin from damaging ultraviolet rays mayalso be included. Preferred sunscreens are those with a broad range ofUVB and UVA protection, such as octocrylene, avobenzone (Parsol 1789),octyl methoxycinnamate, octyl salicylate, oxybenzone, homosylate,benzophenone, camphor derivatives, zinc oxide, and titanium dioxide.When present, the sunscreen may comprise from about 0.01 wt % to about70 wt % of the composition.

Suitable exfoliating agents include, for example, alpha-hydroxyacids,beta-hydroxyacids, oxaacids, oxadiacids, and their derivatives such asesters, anhydrides and salts thereof. Suitable hydroxy acids include,for example, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, 2-hydroxyalkanoic acid, mandelic acid, salicylic acid andderivatives thereof. A preferred exfoliating agent is glycolic acid.When present, the exfoliating agent may comprise from about 0.1 wt % toabout 80 wt % of the composition.

An antioxidant functions, among other things, to scavenge free radicalsfrom skin to protect the skin from environmental aggressors. Examples ofantioxidants that may be used in the present compositions includecompounds having phenolic hydroxy functions, such as ascorbic acid andits derivatives/esters; beta-carotene; catechins; curcumin; ferulic acidderivatives (e.g. ethyl ferulate, sodium ferulate); gallic acidderivatives (e.g., propyl gallate); lycopene; reductic acid; rosmarinicacid; tannic acid; tetrahydrocurcumin; tocopherol and its derivatives;uric acid; or any mixtures thereof. Other suitable antioxidants arethose that have one or more thiol functions (—SH), in either reduced ornon-reduced form, such as glutathione, lipoic acid, thioglycolic acid,and other sulfhydryl compounds. The antioxidant may be inorganic, suchas bisulfites, metabisulfites, sulfites, or other inorganic salts andacids containing sulfur. Compositions of the present invention maycomprise an antioxidant preferably from about 0.001 wt % to about 10 wt%, and more preferably from about 0.01 wt % to about 5 wt %, of thetotal weight of the composition.

Other conventional additives include: vitamins, such as tocopherol andascorbic acid; vitamin derivatives such as ascorbyl monopalmitate;thickeners such as hydroxyalkyl cellulose; gelling agents; structuringagents such as bentonite, smectite, magnesium aluminum silicate andlithium magnesium silicate; metal chelating agents such as EDTA;pigments such as zinc oxide and titanium dioxide; colorants; emollients;and humectants.

It is preferred that the composition be essentially free of componentshaving a strong oxidizing potential, including for example, organic orinorganic peroxides. By “essentially free of” these components is meantthat the amounts present are insufficient to have a measurable impact onthe collagen enhancing activity of the N-substitutedsulfonyloxybenzylamine. In some embodiments, this will be, on a molarbasis in relation to the amount of N-substituted sulfonyloxybenzylamine,less than 1%.

In one embodiment, the composition of the invention comprising anN-substituted sulfonyloxybenzylamine may have a pH between about 1 andabout 8. In certain embodiments, the pH of the composition will beacidic, i.e., less than 7.0, and preferably will be between about 2 andabout 7, more preferably between about 3.5 and about 5.5.

The invention provides a method for treating aging skin by topicallyapplying a composition comprising a N-substitutedsulfonyloxybenzylamine, preferably in a cosmetically acceptable vehicle,over the affected area for a period of time sufficient to reduce,ameliorate, reverse or prevent dermatological signs of aging. Thismethod is particularly useful for treating signs of skin photoaging andintrinsic aging.

Generally, the improvement in the condition and/or aesthetic appearanceis selected from the group consisting of: reducing dermatological signsof chronological aging, photo-aging, hormonal aging, and/or actinicaging; preventing and/or reducing the appearance of lines and/orwrinkles; reducing the noticeability of facial lines and wrinkles,facial wrinkles on the cheeks, forehead, perpendicular wrinkles betweenthe eyes, horizontal wrinkles above the eyes, and around the mouth,marionette lines, and particularly deep wrinkles or creases; preventing,reducing, and/or diminishing the appearance and/or depth of lines and/orwrinkles; improving the appearance of suborbital lines and/orperiorbital lines; reducing the appearance of crow's feet; rejuvenatingand/or revitalizing skin, particularly aging skin; reducing skinfragility; preventing and/or reversing of loss of glycosaminoglycansand/or collagen; ameliorating the effects of estrogen imbalance;preventing skin atrophy; preventing, reducing, and/or treatinghyperpigmentation; minimizing skin discoloration; improving skin tone,radiance, clarity and/or tautness; preventing, reducing, and/orameliorating skin sagging; improving skin firmness, plumpness,suppleness and/or softness; improving procollagen and/or collagenproduction; improving skin texture and/or promoting retexturization;improving skin barrier repair and/or function; improving the appearanceof skin contours; restoring skin luster and/or brightness; minimizingdermatological signs of fatigue and/or stress; resisting environmentalstress; replenishing ingredients in the skin decreased by aging and/ormenopause; improving communication among skin cells; increasing cellproliferation and/or multiplication; increasing skin cell metabolismdecreased by aging and/or menopause; retarding cellular aging; improvingskin moisturization; enhancing skin thickness; increasing skinelasticity and/or resiliency; enhancing exfoliation; improvingmicrocirculation; decreasing and/or preventing cellulite formation; andany combinations thereof.

Without wishing to be bound by any particular theory, it is believedthat the compositions of the present invention enhance and improve theaesthetic appearance of skin by stimulation of collagen and/or byimproving the cell-to-cell adhesion between keratinocytes through thestimulation of Desmogleins.

The composition will typically be applied to the skin one, two, or threetimes daily for as long as is necessary to achieve desired anti-agingresults. The treatment regiment may comprise daily application for atleast one week, at least two weeks, at least four weeks, at least eightweeks, or at least twelve weeks. Chronic treatment regimens are alsocontemplated.

The N-substituted sulfonyloxybenzylamine active component is topicallyapplied to an “individual in need thereof,” by which is meant anindividual that stands to benefits from reducing visible signs of skindamage or aging. In a specific embodiment, the N-substitutedsulfonyloxybenzylamine component is provided in a pharmaceutically,physiologically, cosmetically, and dermatologically-acceptable vehicle,diluent, or carrier, where the composition is topically applied to anaffected area of skin and left to remain on the affected area in anamount effective for improving the condition and aesthetic appearance ofskin.

In one embodiment, methods for treating fine lines and wrinkles comprisetopically applying the inventive N-substituted sulfonyloxybenzylaminecompositions to the skin of an individual in need thereof, e.g.,topically application directly to the fine line and/or wrinkle in anamount and for a time sufficient to reduce the severity of the finelines and/or wrinkles or to prevent or inhibit the formation of new finelines and/or wrinkles. The effect of a composition on the formation orappearance of fine lines and wrinkles can be evaluated qualitatively,e.g., by visual inspection, or quantitatively, e.g., by microscopic orcomputer assisted measurements of wrinkle morphology (e.g., the number,depth, length, area, volume and/or width of wrinkles per unit area ofskin). This embodiment includes treatment of wrinkles on the skin of thehands, arms, legs, neck, chest, and face, including the forehead,

It is also contemplated that the compositions of the invention will beuseful for treating thin skin by topically applying the composition tothin skin of an individual in need thereof. “Thin skin” is intended toinclude skin that is thinned due to chronological aging, menopause, orphoto-damage. In some embodiments, the treatment is for thin skin inmen, whereas other embodiments treat thin skin in women, pre-menopausalor post-menopausal, as it is believed that skin thins differently withage in men and women, and in particular in women at different stages oflife.

The method of the invention may be employed prophylactically toforestall aging including in patients that have not manifested signs ofskin aging, most commonly in individuals under 25 years of age. Themethod may also reverse or treat signs of aging once manifested as iscommon in patients over 25 years of age.

The following examples are meant to demonstrate certain aspects of theinvention in a non-limiting fashion.

EXAMPLES Example 1 Collagen Assay

Human dermal fibroblasts (Cascade Biologics, Portland, Oreg.) wereplated at 10,000 cells/well in 96-well culture plates in supplementedmedium (DMEM, 10% Fetal Bovine Serum, 1% Penicillin/Streptomycin and 1%L-Glutamine) overnight in humidified atmosphere of 10% CO₂ at 37° C. Thenext day, the medium was replaced with fresh medium (DMEM, 1%Penicillin/Streptomycin and 1% L-Glutamine) and the compounds dissolvedin DMSO were added to the wells in triplicate at a concentration of0.0005%. DMSO solution was used a control. Following 48-hour incubation,the plates were removed from the incubator and the medium from each wellwas collected for the procollagen assay.

Collagen production was measured using procollagen type I C-peptide(PIP) EIA kit (Takara Bio, Inc., Japan). Briefly, the conditioned mediumwas diluted 1:10 in Sample Diluent. 20 μl of diluted conditioned mediumand 100 μl of antibody-POD conjugate solution were added to the wells ofthe Takara ELISA plate. The ELISA plate was incubated at 37° C. for 3hours before the wells were washed four times with 400 μl of 1×PBS. Atthe end of wash, 100 μl of substrate solution (supplied with kit) wasadded to the wells and incubated at room temperature for 15 minutes. Thereaction was stopped by adding 100 μl of 1N sulfuric acid to the wells.The absorbance was measured on a spectrophotometer at 450 nm wavelength.The amount of procollagen peptide in the conditioned medium wascalculated from the standard curve. The stimulation of collagenproduction was shown as an increase in collagen over the control.

The results of compounds tested in the collagen assay are illustrated inTable 1:

TABLE 1 Analogs active at stimulating collagen synthesis

Stimulation Com- of pound collagen Number Position R₁ R₂ R₃ production*1 4 CH₃ i-butyl SO₂Phenyl ++++ 2 4 CH₃ i-butyl CONH(2-Et)Ph ++++ 3 3CH₂CH₃ CH₂-2- CONH-c-hexyl +++ furanyl 4 3 CH₂CH₃ s-butyl CO(4-OCH₃)Ph+++ 5 3 CH₃ Methoxy- CO(4-Cl)Ph +++ ethyl 6 3 CH₃ i-butyl CObutyl +++ 73 CH(CH₃)₂ i-butyl CO-i-butyl ++++ 8 4 CH₂CH₃ i-butyl CO-c-propyl ++++ 93 CH₂CH₃ i-propyl CONH-t-butyl +++ 10  3 CH(CH₃)₂ i-butyl CO-c-butyl +++“+++” 51-80% increase in collagen over control; “++++” >81% increase incollagen over control

All references including patent applications and publications citedherein are incorporated herein by reference in their entirety and forall purposes to the same extent as if each individual publication orpatent or patent application was specifically and individually indicatedto be incorporated by reference in its entirety for all purposes. Manymodifications and variations of this invention can be made withoutdeparting from its spirit and scope, as will be apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only, and the invention is to be limited onlyby the terms of the appended claims, along with the full scope ofequivalents to which such claims are entitled.

The invention claimed is:
 1. A method for improving the aestheticappearance of human skin comprising topically applying to an area of theskin in need thereof an effective amount of an N-substitutedsulfonyloxybenzylamine or a cosmetically acceptable salt thereof in acosmetically acceptable vehicle.
 2. The method according to claim 1wherein said N-substituted sulfonyloxybenzylamine has the structure offormula I:

where: W₁ and W₂ are independently CO, CO₂, CONH, SO₂ or PO₃; R₁, R₂ andR₃ are independently C₁₋₂₀ hydrocarbons, each independently selectedfrom alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, heteroalkyl, heteroaryl,aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, andalkylheteroaryl, each being optionally substituted with C and/or 1-6heteroatoms, including halogen, O, N and S; X, Y each independentlyrepresent H or an optionally substituted alkyl, haloalkyl, alkoxy,amino, aminoalkyl, haloalkoxy, alkenyl, and where adjacent X, Y takentogether can form a 5, 6, or 7 member ring; and wherein the —O—W₂—R₁group is attached to the phenyl ring at the 3- or 4-position.
 3. Themethod according to claim 2, where R₁ is a C₁₋₄ alkyl group.
 4. Themethod according to claim 3, where R₁ is —CH₃ or —CH₂CH₃.
 5. The methodaccording to claim 2, where R₂ is selected from the group consisting ofi-butyl, sec-butyl, methoxyethyl and CH₂-2-furanyl.
 6. The methodaccording to claim 5, where R₂ is a group i-butyl.
 7. The methodaccording to claim 2, where W₁ and W₂ are independently selected fromthe group consisting of CO, CONH, and SO₂.
 8. The method according toclaim 7, where W₁ is a group —SO₂ or a group —CONH, and W₂ is a group—SO₂.
 9. The method according to claim 2, where R₃ is alkyl, cycloalkylor aryl.
 10. The method according to claim 9, where R₃ is phenyl. 11.The method according to claim 1, wherein said aesthetic improvement ofsaid human skin is selected from the group consisting of: (a) treatmentand/or reduction of fine lines or wrinkles, (b) reduction of skin poresize, (c) improvement in skin thickness, plumpness, and/or tautness; (d)improvement in skin suppleness and/or softness; (e) improvement in skintone, radiance, and/or clarity; (f) improvement in procollagen and/orcollagen production; (g) improvement in maintenance and remodeling ofelastin; (h) improvement in skin texture and/or promotion ofretexturization; (i) improvement in skin barrier repair and/or function;(j) improvement in appearance of skin contours; (k) restoration of skinluster and/or brightness; (l) replenishment of essential nutrientsand/or constituents in the skin; (m) improvement of skin appearancedecreased by menopause; (n) improvement in skin moisturization; (o)increase in skin elasticity and/or resiliency; (p) treatment and/orreduction of skin sagging; and (q) reduction of pigment spots.
 12. Themethod according to claim 11, wherein said aesthetic improvement of saidskin is the treatment and/or reduction of: fine lines and/or wrinkles,skin sagging, loss of elasticity and mottled skin appearance.
 13. Themethod according to claim 2, wherein said N-substitutedsulfonyloxybenzylamine has the structure:

or a cosmetically acceptable salt thereof, where: X and Y are H; R₁ is aC₁₋₈ alkyl group, a phenyl group or benzyl group, each being optionallysubstituted with C and/or 1-6 heteroatoms, including halogen, O, N andS; R₂ is alkyl, aryl, alkylaryl or heteroaryl, each being optionallysubstituted with C and/or 1-6 heteroatoms, including halogen, O, N andS; and R₃ is alkyl or aryl, each being optionally substituted with Cand/or 1-6 heteroatoms, including halogen, O, N and S.
 14. The methodaccording to claim 2, wherein said N-substituted sulfonyloxybenzylaminehas the structure:

or a cosmetically acceptable salt thereof, where X and Y are H; R₁ is aC₁₋₈ alkyl group, a phenyl group or benzyl group, each being optionallysubstituted with C and/or 1-6 heteroatoms, including halogen, O, N andS; R₂ is alkyl, aryl, alkylaryl or heteroaryl each being optionallysubstituted with C and/or 1-6 heteroatoms, including halogen, O, N andS; and R₃ is alkyl or aryl each being optionally substituted with Cand/or 1-6 heteroatoms, including halogen, O, N and S; and wherein said—O—SO₂—R₁ group is attached to the phenyl ring at the 3- or 4-position.15. The method according to claim 2, wherein said N-substitutedsulfonyloxybenzylamine has the structure:

where: X and Y are H; R₁ is a C₁₋₈ alkyl group, a phenyl group or benzylgroup, each being optionally substituted with C and/or 1-6 heteroatoms,including halogen, O, N and S; R₂ is alkyl, aryl, alkylaryl orheteroaryl, each being optionally substituted with C and/or 1-6heteroatoms, including halogen, O, N and S; and R₃ is alkyl or aryl,each being optionally substituted with C and/or 1-6 heteroatoms,including halogen, O, N and S.
 16. A method for treating wrinkles and/orfine lines comprising topically applying to said wrinkle and/or fineline on the skin of an individual in need thereof an effective amount ofa N-substituted sulfonyloxybenzylamine or a cosmetically acceptable saltthereof in a cosmetically acceptable vehicle for a time sufficient toreduce the severity of said wrinkles or fine lines.
 17. The methodaccording to claim 16, wherein said N-substituted sulfonyloxybenzylamineor a cosmetically acceptable salt thereof is applied to said skin atleast once daily for a period of at least four weeks.
 18. The methodaccording to claim 15, wherein said N-substituted sulfonyloxybenzylaminehas the structure:

or a cosmetically acceptable salt thereof.
 19. The method according toclaim 16 wherein said N-substituted sulfonyloxybenzylamine has thestructure of formula I:

where: W₁ and W₂ are independently CO, CO₂, CONH, SO₂ or PO₃; R₁, R₂ andR₃ are independently C₁₋₂₀ hydrocarbons, each independently selectedfrom alkyl, cycloalkyl, haloalkyl, alkoxyalkyl, heteroalkyl, heteroaryl,aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, andalkylheteroaryl, each being optionally substituted with C and/or 1-6heteroatoms, including halogen, O, N and S; X, Y each independentlyrepresent H or an optionally substituted alkyl, haloalkyl, alkoxy,amino, aminoalkyl, haloalkoxy, alkenyl, and where adjacent X, Y takentogether can form a 5, 6, or 7 member ring; and wherein the —O—W₂—R₁group is attached to the phenyl ring at the 3- or 4-position.